Potentiating tumor immunity using aptamer-targeted RNAi to render CD8⁺ T cells resistant to TGFβ inhibition

Area of Science:

• Immunology
• Cancer Biology
• Molecular Therapy

Background:

• Transforming growth factor-beta (TGFβ) secreted by tumors promotes tumor growth and immune suppression.
• Clinical trials targeting TGFβ have shown limited success due to its essential physiological roles, preventing dose escalation.
• Countering TGFβ's immunosuppressive effects is a potential strategy for inhibiting tumor growth.

Purpose of the Study:

• To develop a method for transiently rendering vaccine-activated CD8+ T cells resistant to TGFβ inhibition.
• To assess the efficacy of targeting the canonical TGFβ signaling pathway via Smad4 inhibition in T cells.
• To evaluate the therapeutic potential of a novel 4-1BB-Smad4 conjugate in enhancing anti-tumor immunity.

Main Methods:

• Utilized small interfering RNA (siRNA) against Smad4 to block TGFβ signaling.
• Conjugated siRNA to a 4-1BB binding aptamer ligand for targeted delivery to vaccine-activated CD8+ T cells in mice.
• Administered the 4-1BB-Smad4 conjugate systemically to tumor-bearing mice.

Main Results:

• The 4-1BB-Smad4 conjugate partially conferred TGFβ resistance to T cells *in vitro*.
• Systemic administration of the conjugate enhanced vaccine- and irradiation-induced anti-tumor immunity in mice.
• The targeted approach aims to limit TGFβ inhibition to tumor-specific T cells, minimizing interference with physiological functions.

Conclusions:

• Targeting TGFβ signaling in T cells offers a promising strategy to overcome tumor-induced immunosuppression.
• The 4-1BB-Smad4 conjugate demonstrates potential for enhancing cancer immunotherapy by improving T cell function.
• This approach may reduce the toxicity associated with systemic TGFβ inhibition, allowing for more effective anti-tumor responses.